The goal of the Vaaderbilt O'Brien Center for Kidney Diseases is to elucidate mechanisms of progressive glomerular and tubulointerstitialinjury and identify potential therapeutic interventions to retard or prevent progressive nephron destruction. In our submission for funding for years 16-20, the Center is composed of four projecls, two scientific cores and an administrative core. In addition, we include three new Pilot and Feasibility Projects. Project #1 will study the development of glomerular sclerosis in the aging kidney and will investigate the role of the renin-angiotensin system and its interactions with the fibrinolytic system and cyclooxygenase-2 in mediation of the increased glomerular ECM deposition. Project #2 will investiga:e the role of cortical cyclooxygenase-2 expression in the kidney cortex in both inflammatory and "non-inflammatory" progressive renal injury. The aims of this proposal are designed to address mechanisms of regulation of COX-2 expression and the pathophysiologic consequences of increased expression in the macula densa and surrounding cTALH, infiltrating leukocytes in glomerulus and tubulointerstitiumarid glomerular podocytes. Project #3 will identify and study the cyclooxygenase metabolites mediating renal growth, function and injury in development and progressive nephron injury. Project #4 will examine mechanisms underlying development of diabetic renal microangiopathy, and specifically the role of vascular endothelial growth factor (VEGF) and VEGF receptor signaling. The two scientific cores interact v/ith all four of the projects and with the three pilot projects to provide support for genotyping and phenotyping genetically engineered animal models, access to histologic preparation and analysis of samples and quantitative morphometric support. We believe that this group of investigators brings together significant scientific expertise and diverse and complementary techniques and experimental approaches that will produce a cohesive and focused effort to further identify mechanisms and potential therapeutic targets to retard progressive nephron destruction.